Introduction

Guillain-Barré syndrome (GBS) is an acute acquired autoimmune inflammatory disorder of the peripheral nerves and roots [1]. Pathogenesis is essentially an aberrant post-infection immune response in a genetically susceptible host milieu [2]. GBS is clinically subdivided into acute inflammatory demyelinating polyradiculoneuropathy (AIDP), acute motor axonal neuropathy (AMAN), acute motor sensory axonal polyneuropathy (AMSAN), and less common variants, such as Miller Fisher syndrome and Bickerstaff encephalitis. Respiratory failure resulting from impaired secretion clearance and respiratory muscle weakness is the most common complication, affecting 20% to 30% of patients [3]. Respiratory support is required in 14% to 44% of patients with GBS during the course of illness, with a reported mortality of 5% to 10%, mostly due to autonomic failure and respiratory failure [4]. Respiratory failure requiring mechanical ventilation could be due to diaphragmatic paresis, overuse of accessory respiratory muscles, retained orobronchial secretions, atelectasis, or immobilization. Furthermore, hypercarbia and hypoxia can develop insidiously in patients with GBS, and delaying intubation until the traditional signs of respiratory failure emerge may increase the risk of emergency intubation and associated complications, including aspiration [5]. Therefore, the optimal management of respiratory failure in GBS requires timely intubation. Anticipating respiratory failure and prompt intervention are associated with reduced complication rates and improved patient outcomes.

Clinicopathological predictors of respiratory failure in GBS have not been strongly validated. Studies have attempted to evaluate phrenic nerve conduction, needle electromyography of the diaphragm muscle, and forced vital capacity in the evolution of respiratory insufficiency in patients with GBS with composite results [6,7]. Hence, this prospective study aimed to determine the value of the phrenic nerve conduction study (NCS) in predicting respiratory failure in GBS. In addition, we attempted to determine the impact of the initial phrenic NCS on the follow-up outcomes of patients at 6 months.

Methods

Ethics statement: The Institutional Review Board (IRB) approved the study protocol (IRB No: ECR/262/Inst/UP/2013/RR-19), and a written informed consent was obtained from all the patients/legal guardians.

This was a prospective study conducted from December 2019 to November 2022 in the Department of Neurology, King George’s Medical University, Lucknow, India.

All patients diagnosed with GBS based on the consensus diagnostic criteria proposed by Brighton and presenting within 2 weeks of onset were included [8]. Patients with a spinal shock state of acute myelitis, hypokalemic or hyperkalemic periodic paralysis, porphyria, botulism, rabies, or any other cause of acute neuropathies were excluded. The primary outcome was respiratory failure requiring ventilator assistance after admission. Patients who were already intubated at admission, required intensive care, or died in the intensive care facility were also excluded from the study.

The clinical parameters analyzed included age, sex, antecedent infection, duration of illness, time to peak limb weakness, respiratory involvement, bulbar involvement, cranial nerve involvement, autonomic involvement, single breath count (SBC), duration of hospital stay, complications, ventilatory requirement, and case fatality.

The degree of limb weakness was determined by calculating the Medical Research Council (MRC) sum score as the sum of the MRC grades (range, 0–5) of six muscle pairs noted bilaterally: the upper arm abductors, elbow flexors, wrist extensors, hip flexors, knee extensors, and foot dorsiflexors. The MRC sum score ranges from 0 (tetraplegia) to 60 (no paralysis) [9].

Patients who developed arrhythmias, fluctuating heart rate and blood pressure including orthostatic hypotension, abnormal sweating, pupillary abnormalities, gastrointestinal dysfunction, and urinary disturbances, were considered to have autonomic dysfunction. Respiratory involvement was recognized in patients developing dyspnea, tachypnea, abnormal breathing patterns, paradoxical breathing, increased use of accessory breathing muscles, hypoxemia, reduced SBC <30/minute, or combinations thereof. Patients who developed the use of accessory muscles for breathing, clinical features of hypoxia, and arterial blood gas analysis abnormalities (partial pressure of oxygen, <70 mmHg; partial pressure of carbon dioxide, >45 mmHg) were deemed to have respiratory failure, were immediately intubated, and provided mechanical ventilator assistance.

The NCS was performed using Synergy, ver. 14.0 (2005; VIASYS Healthcare UK Ltd., Middlesex, UK). Motor NCSs of the bilateral median, ulnar, tibial, peroneal, and phrenic nerves were performed. Sensory NCSs were performed bilaterally on the median, ulnar, and sural nerves. Each NCS was analyzed using criteria suggested by Hadden et al. [10] as demyelinating, axonal, or inexcitable. The GBS typing was confirmed after repeating the NCS after 1 week (whenever required).

Phrenic nerve conduction was studied within 24 hours of admission, along with standard NCS of all four limbs using an electromyography machine (model Max-280VA; Nihon Kohden Corp., Tokyo, Japan), according to the procedure described by Davis [11]. The patient was positioned supine with the head slightly extended and rotated contralateral to the side of the phrenic nerve stimulation. The stimulus was a rectangular pulse (duration of 0.2–1.0 ms), which was delivered at a frequency of 1 Hz. The phrenic nerve was percutaneously stimulated at the posterior border of the sternocleidomastoid approximately 3 cm above the neck clavicle. The surface recording electrodes were placed 16 cm apart, with G1 (active electrode) placed two fingerbreadths above the xiphoid process, G2 (reference electrode) placed on the anterior costal margin, and the ground electrode attached over the anterior chest wall. The intensity of electrical stimulation was increased until no additional increase in the diaphragm compound muscle action potential (CMAP) amplitude was observed. Then, three supramaximal stimulations were delivered to each phrenic nerve at the end of expiration, and the mean value was calculated. The latency of diaphragmatic CMAP was measured from the stimulus artifact to the onset of CMAP. The duration, peak-to-peak amplitude, and area of the diaphragmatic CMAP were also determined. Any value beyond the normal value of phrenic nerve CMAP latency (upper limit, 8.0 ms), amplitude (lower limit, 0.33 mV), area (lower limit, 4.4 mV·ms), and duration (upper limit, 25 ms) was considered to be abnormal phrenic NCS [12]. Additionally, abnormal phrenic nerve study patterns were subtyped as axonal, demyelinating, or inexcitable.

All patients were treated with intravenous immunoglobulin or plasma exchange as per the standard regimen. Patients were carefully monitored for early respiratory deterioration; endotracheal mechanical ventilation was routinely used in patients who met the criteria for respiratory failure [13]. Early physiotherapy was recommended in all cases. Patients were followed up at 1, 3, and 6 months, and outcomes were assessed using the Hughes disability score [13].

Quantitative data were entered into Microsoft Excel and exported to IBM SPSS ver. 19.0 (IBM Corp., Armonk, NY, USA) for analysis. Data were analyzed using t-tests and Mann-Whitney U tests between the groups with and without ventilatory assistance, and p-values were considered significant if <0.05. Univariate factors predictive of respiratory failure were assessed using the chi-square test for categorical variables. Multivariate logistic regression analysis using a backward elimination procedure was used to determine independent predictors of respiratory failure in patients with GBS. Ventilator support assistance was the dependent variable, and all variables found to have a p-value <0.02 by univariate analysis were included in the model as independent variables. All significant variables were entered into the model in the first step. The most nonsignificant variable was then removed, and all remaining variables were entered into the model in the second step. This procedure was repeated until the remaining variables contributed significantly (p<0.05) to the prediction of outcomes.

Results

1. Clinical characteristics

A total of 207 patients presented with acute flaccid paralysis, among which 135 patients were enrolled in the study as shown in the flowchart schematic (Fig. 1). The mean age of the cases was 31.74±4.61 years, with a male:female ratio of 1.76:1 and an antecedent history of infection in 73 patients (54.1%). Various types of GBS such as AIDP, AMAN, AMSAN, and inexcitable were observed in 44, 42, 31, and 18 patients, respectively. Respiratory and autonomic involvement occurred in 58 patients (43.0%) and 64 patients (47.4%), respectively, while respiratory failure requiring mechanical ventilation occurred in 43 patients (31.9%) and 14 patients (10.4%) died (Table 1). The time interval between admission and intubation in patients requiring mechanical ventilation was 2.52±2.14 days.

2. Phrenic nerve study

Phrenic nerve abnormalities occurred in 48 patients (35.6%), with phrenic nerve inexcitability observed in eight cases, axonal pattern in 26 cases, and demyelinating pattern in 14 cases. The patients with GBS but without respiratory failure showed a sum phrenic CMAP latency of 8.52±0.37 ms, sum CMAP amplitude of 0.760±0.190 mV, sum CMAP duration of 17.84±7.26 ms, and sum CMAP area of 5.38±3.42 mV·ms. These indices were significantly altered in patients with GBS and respiratory failure requiring mechanical ventilation, showing an increased phrenic sum CMAP latency (18.91±7.82 ms), reduced sum CMAP amplitude (0.324±0.132 mV), increased sum CMAP duration (44.65±6.84 ms), and reduced sum CMAP area (3.56±2.62 mV·ms) (Table 2). The sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, and negative likelihood ratio of the phrenic NCS for predicting respiratory involvement in patients with GBS were 90.7%, 90.2%, 81.3%, 95.4%, 9.27, and 0.10, respectively (Table 3).

3. Outcome analysis

The predictors of respiratory failure requiring ventilatory support in patients with GBS are presented in Table 4. On univariate analysis, antecedent infection, cranial neuropathy, autonomic involvement, bulbar involvement within 6 days, SBC <10/minute, initial MRC score <30, albuminocytological dissociation, axonal GBS, abnormal phrenic NCS, phrenic CMAP latency >8 ms, CMAP amplitude <0.33 mV, CMAP duration >28 ms, and CMAP area <4.4 mV·ms were found to be associated with respiratory failure. Multivariate analysis was also performed using binary logistic regression, where the occurrence of cranial neuropathy, bulbar involvement within 6 days, SBC <10/minute, initial MRC score <30, abnormal phrenic NCS, phrenic sum CMAP latency >8 ms, CMAP amplitude <0.33 mV, CMAP duration >28 ms, and CMAP area <4.4 mV·ms were found to be independently related to respiratory failure.

The outcomes of patients with GBS were further assessed at 1, 3, and 6 months as per the Hughes disability scale, and the comparison was analyzed in patients with abnormal initial phrenic NCS and the lowest SBC of <10/minute at hospitalization (Table 5). The results showed a statistically significant association between an abnormal initial phrenic NCS and the prognostic outcomes in patients with GBS (p<0.001). However, the lowest SBC of <10/minute was not statistically significant for outcomes in patients with GBS.

Discussion

This prospective study described the significance of the phrenic NCS in GBS in predicting respiratory failure and the need to consider mechanical ventilation. To the best of our knowledge, this is the largest prospective study of phrenic NCS on GBS to date with an outcome analysis. Statistical analysis of the phrenic NCS in the present study revealed a significant increase in sum latency, reduced sum amplitude, increased sum duration, and decreased sum area in patients with respiratory failure. In addition, phrenic NCS has shown the potential for predicting respiratory failure with good sensitivity, specificity, predictive value, and likelihood ratio for mechanical ventilator assistance in GBS. Furthermore, variables such as cranial neuropathy, bulbar involvement within 6 days, SBC <10/minute, initial MRC score <30, abnormal phrenic NCS, phrenic sum CMAP latency >8 ms, CMAP amplitude <0.33 mV, CMAP duration >28 ms, and CMAP area <4.4 mV·ms were independently associated with respiratory failure. Finally, an initial abnormal phrenic NCS showed a statistically significant association with outcomes at 6 months in patients with GBS. As a subjective test, the SBC may not be attributed efficiently in comparison to a quantitative test, such as the phrenic nerve study in GBS.

Respiratory failure is considered to be a prominent cause of morbidity and mortality in GBS [14]. The criteria for elective intubation in patients with GBS and bulbar weakness, vital capacity <15 mL/kg, and partial pressure of oxygen on room air <70 mmHg were developed by Ropper and Kehne [15]. In the 20-30-40 rule, as stated by Lawn et al. [16], a patient’s vital capacity, maximum inspiratory pressure, and maximum expiratory pressure were all taken into consideration if they were below 20, 30, and 40 mL/kg, respectively. Phrenic NCS is known to evaluate respiratory function in patients who are critically ill [17-19]. The electrophysiological study of phrenic nerves was initially described by Davis [11], with only minimal modifications by Preston and Shapiro [20]. The assessment and utility of phrenic nerve studies in patients with GBS in the past are summarized in Table 6.

In the paradigm study by Gourie-Devi and Ganapathy [21] in 1985, abnormalities in phrenic nerve conduction time were observed in 64.3% of patients with GBS, of which 83.3% were found to develop ventilatory failure during the course of illness. Zifko et al. [6] studied phrenic NCS and diaphragmatic electromyograms in 40 patients with GBS and found that the diaphragmatic CMAP amplitude and area under the curve correlated with the need for respiratory support in these patients, while the diaphragmatic CMAP latency and duration were unrelated to respiratory failure. However, another French study by Durand et al. [7] observed contradictory findings that phrenic NCS abnormalities did not reflect diaphragm weakness in patients with GBS and that clinical acumen and vital capacity measurements predicted respiratory failure. A subsequent Japanese study by Ito et al. [22] found that all the patients with GBS with a sum of phrenic nerve latency >30 ms and a sum of the bilateral diaphragmatic CMAP amplitude <0.3 mV required respiratory assistance. However, the sample size in the study was small (15 patients) and a larger prospective study could provide better evidence in validating the role of phrenic NCS in patients with GBS. In an Iranian study by Basiri et al. [23], it was observed that phrenic nerve CMAP latency and amplitude, and diaphragmatic CMAP duration can be predictive of respiratory failure in patients with GBS.

In a recent study by Sen and Pandit [12], global abnormalities in the phrenic nerve sum latency, amplitude, duration, and area were observed in patients with GBS who developed respiratory failure during their hospital stay. Furthermore, a sum of phrenic nerve latency >28 ms, sum of phrenic nerve CMAP amplitude <300 μV, sum of CMAP duration >50 ms, and sum of area <4 mV·ms predicted the need for respiratory assistance in the form of mechanical ventilation. They also found that SBC was significantly lower in the patients with GBS who developed respiratory failure.

The strength of the present study is that it is the largest prospective phrenic NCS in GBS. This study included both children and older individuals with GBS. All patients underwent phrenic NCS examination by the same observer. All data were obtained with no loss to follow-up. In addition, to the best of our knowledge, this is the only phrenic NCS with a 6-month follow-up duration to assess GBS outcomes. A limitation of the present study is that spirometry analysis of vital capacity, electromyography of the diaphragm, and follow-up phrenic NCS were not performed.

The phrenic NCS is a highly sensitive parameter for determining impending respiratory failure in patients with GBS. The inclusion of phrenic nerve studies in routine NCS can have a beneficial impact on morbidity and mortality outcomes in these patients.

Article information

Conflicts of interest

No potential conflict of interest relevant to this article was reported.

Funding

None.

Author contributions

Conceptualization, Formal analysis: all authors; Data curation: RC, RV, AK, PB, AC; Validation: RV; Methodology: RC, SKC, AK, SS, PB, AC; Project administration: HN; Visualization: HN, SS, AC; Investigation: RC, AK, SS, AC; Resources: RC, AK; Software: PB, AC; Supervision: RV, SKC, HN, PB; Writing-original draft: RC, SKC, HN, AK, SS, PB, AC; Writing-review & editing: RC, RV.

Fig. 1.

Flowchart of the study. GBS, Guillain-Barré syndrome; NCS, nerve conduction study.

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Figure & Data

References

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